Processes for the preparation of uracil derivatives

ABSTRACT

The present invention relates to processes and intermediates for preparing Gonadotropin-Releasing Hormone (GnRH) receptor antagonists of structure (VI); and stereoisomers and pharmaceutically acceptable salts thereof.

FIELD OF THE INVENTION

The present invention relates to processes for the preparation of uracilderivatives which may be useful as gonadotropin-releasing hormonereceptor antagonists.

BACKGROUND OF THE INVENTION

Gonadotropin-releasing hormone (GnRH), also known as luteinizinghormone-releasing hormone (LHRH), is a decapeptide(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂) that plays an importantrole in human reproduction. GnRH is released from the hypothalamus andacts on the pituitary gland to stimulate the biosynthesis and release ofluteinizing hormone (LH) and follicle-stimulating hormone (FSH). LHreleased from the pituitary gland is responsible for the regulation ofgonadal steroid production in both males and females, while FSHregulates spermatogenesis in males and follicular development infemales.

Due to its biological importance, synthetic antagonists and agonists toGnRH have been the focus of considerable attention, particularly in thecontext of prostate cancer, breast cancer, endometriosis, uterineleiomyoma (fibroids), ovarian cancer, prostatic hyperplasia, assistedreproductive therapy, and precocious puberty (The Lancet 358:1793-1803,2001; Mol. Cell. Endo. 166:9-14, 2000). For example, peptidic GnRHagonists, such as leuprorelin(pGlu-His-Trp-Ser-Tyr-d-Leu-Leu-Arg-Pro-NHEt), have been used to treatsuch conditions. Such agonists appear to function by binding to the GnRHreceptor in the pituitary gonadotropins, thereby inducing the synthesisand release of gonadotropins. Chronic administration of GnRH agonistsdepletes gonadotropins and subsequently down-regulates the receptor,resulting in suppression of steroidal hormones after some period of time(e.g., on the order of 2-3 weeks following initiation of chronicadministration).

In contrast, GnRH antagonists are believed to suppress gonadotropinsfrom the onset, and thus have received the most attention over the pasttwo decades. To date, some of the primary obstacles to the clinical useof such antagonists have been their relatively low bioavailability andadverse side effects caused by histamine release. However, severalpeptidic antagonists with low histamine release properties have beenreported, although they still must be delivered via sustained deliveryroutes (such as subcutaneous injection or intranasal spray) due tolimited bioavailability.

The present invention relates to synthetic routes to produce variousuracil derivatives including the compounds4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-butanoicacid and its sodium and calcium salts,4-[[(1R)-2-[5-(2-chloro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-1-phenylethyl]amino]-butanoicacid and its sodium and calcium salts, and5-iodo-6-methyl-1-(2-methyl-6-trifluoromethyl-benzyl)-1H-pyrimidine-2,4-dione.

Uracil derivatives of formula (I) are described as GnRH antagonists inU.S. Pat. Nos. 6,608,197 and 6,872,728.

Additional uracil derivatives of formula (II) are described in U.S. Pat.No. 7,056,927.

Additional uracil derivatives of formula (III) are described in U.S.Pat. No. 7,015,226.

Additional uracil derivatives of formula (IV) are described in U.S. Pat.No. 7,071,200.

Additional uracil derivatives of formula (V) are described inWO2005007164.

These patents and application are hereby incorporated by reference intheir entirety.

SUMMARY OF THE INVENTION

The present invention provides methods amenable to large scalepreparation of substituted uracil derivatives which are useful as GnRHantagonists. Included are intermediates such as 5-iodo substituteduracils and processes which are useful in preparing uracils of formulas(I) to (V).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides processes for preparing compounds offormula (VI):

or a stereoisomer or pharmaceutically acceptable salt thereof,wherein:

-   -   R_(1a), R_(1b) and R_(1c) are the same or different and        independently hydrogen, halogen, C₁₋₄alkyl, hydroxy or alkoxy;    -   R_(2a) and R_(2b) are the same or different and independently        hydrogen, halogen, trifluoromethyl, cyano or —SO₂CH₃;    -   R₃ is hydrogen or methyl; and    -   R₄ is hydrogen, —C₁₋₆alkanediyl-COOH, or —C(═O)O-(t-butyl).

As used herein, the above terms have the following meaning:

“C₁₋₄alkyl” means a straight chain or branched, noncyclic or cyclichydrocarbon containing from 1 to 4 carbon atoms. Representative straightchain alkyls include methyl, ethyl, n-propyl, n-butyl, and the like;branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, andthe like; while cyclic alkyls include cyclopropyl and the like.

“C₁₋₆alkanediyl” means a divalent C₁₋₆alkyl from which two hydrogenatoms are taken from the same carbon atom or from different carbonatoms, such as —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, and the like.

“Halogen” means fluoro, chloro, bromo or iodo, typically fluoro andchloro.

“Hydroxy” means —OH.

“Alkoxy” means —O—(C₁₋₄alkyl).

“Cyano” means —CN.

In an embodiment, the compounds of formula (VI) may be prepared viaintermediate (VII):

wherein R_(2a), R_(2b) and R₃ are as defined above.

In an embodiment, a compound of formula (VII) may be reacted with acompound of formula (VIII):

Where R is H or C₁₋₄alkyl, R′ is H or C₁₋₄alkyl or R and R′ takentogether form C₁₋₆alkanediyl.

In an embodiment, the compounds of formula VI may be isolated ascrystalline material, amorphic material, or a mixture of both. In anembodiment, amorphic material may be isolated by lyophilization, spraydrying, co-spraying, precipitation or co-precipitation.

In general, the compounds of structure (VI) above may be made by thefollowing reaction schemes, wherein all substituents are as definedabove unless indicated otherwise.

Ureas i may be heated with various acetoacetates ii (such as t-butylacetoacetate as shown) with removal of the generated alcohol to generatean acyclic intermediate which is cyclized to compound iii with an acidcatalyst such as p-toluenesulfonic acid. The acetoacetate ii provides aprocedure which is less hazardous than diketene. Reaction of iii with aniodinating reagent such as iodine monochloride results in compound iv inhigh yield.

Compound iv is coupled with an appropriate boronic acid (such as2-halo-3-methoxyphenyl boronic acid) or boronic acid ester underpalladium catalysis conditions to generate v. Appropriate palladiumsources include palladium acetate andtris(dibenzylidene-acetone)dipalladium(0) while tri-t-butylphosphine andtri-t-butylphosphonium tetrafluoroborate are acceptable phosphineligands. Compound v and mesylate vi react in the presence of a base(such as potassium carbonate or potassium phosphate) to generateBoc-protected material which is deprotected under acidic conditions suchas trifluoroacetic acid in methylene chloride or methanesulfonic acid inisopropyl acetate to yield compound vii.

Compounds of the present invention may exist as amorphous solids. Anamorphous solid is generally defined as a non-crystalline solid in whichmolecules are not organized in a definite lattice.4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid sodium salt (compound 5-1) is an example of a compound of thepresent invention which may be isolated as an amorphous solid. Amorphoussolids may be isolated from various procedures such as lyophilization,spray drying, co-spraying, precipitation or co-precipitation.

Compounds of the present invention, in particular compound 5-1, may beprecipitated as amorphous solids. This precipitation may involveextraction of a compound of formula (VI), in particular compound 5-1,from an aqueous mixture into an organic solvent by adding an appropriateadditive (such as sodium chloride, sodium acetate and sodium hydroxide)to the mixture. Appropriate organic solvents include methylisobutylketone, isopropylacetate and methylethyl ketone. The compound ofinterest may then be precipitated using an appropriate anti-solvent andisolated as an amorphous solid. Appropriate anti-solvents includenonpolar organic solvents such as heptane and hexanes.

These materials may be formulated as amorphous co-solutions where theco-solution may help stabilize the resulting amorphous solid.

Compounds of the present invention may be spray dried by itself or withother excipients such as PVP (polyvinyl pyrrolidone, Kollidon's), HPMC(hydroxypropylmethylcellulose), mannitol, or other suitable carrier.

These procedures may serve to stabilize amorphic material via solidsolution formation with appropriate polymers (Kollidon, HPMC, etc.)resulting from evaporation or grinding techniques.

EXAMPLES Analytical Methods

HPLC Method 1:

Column: Zorbax SB-C18, 3.5μ, 3×150 mm

Mobile Phase A=0.1% trifluoroacetic acid in water

Mobile Phase B=0.1% trifluoroacetic acid in acetonitrile

Gradient Table (data collection stops at 13 min):

Time 0.1% TFA/H₂O 0.1% TFA/CH₃CN Flow Rate 0 70 30 0.75 12.0 10 90 0.7513.0 2.5 97.5 0.75 13.1 70 30 1.2 15.00 70 30 1.2 15.5 70 30 0.75Injection Volume: 2.5 μLColumn Temperature Controlled at 20° C.UV Detection: 220 nm and 254 nm (220 nm data used for all analyses)Diluent: 70:30 CH₃CN:H₂O

Example 1

Step 1A:1-(2-Fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

(2-Fluoro-6-trifluoromethyl-benzyl)-urea (2.568 g, 10.9 mmol) in toluene(125 mL) was heated briefly to reflux under a Dean-Stark trap. T-butylacetoacetate (5.0 g) was added and the mixture heated to reflux for 4hrs. p-Toluenesulfonic acid monohydrate (2.82 g, 14.8 mmol) was addedand the reflux was continued for one additional hour. Toluene wasdisplaced with i-PrOH and the volume of the solution was reduced toapproximately 30 mL. The solution was stirred overnight at room temp.The crystalline product was filtered and washed with a few mL of i-PrOHto provide 2.01 g (63% yield) of1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione.LCMS (ESI) m/z 303.0 (MH+)

Step 1B:1-(2-Fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione

To a 250 mL three-neck round bottom flask was charged1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1a (25.0 g) and methanol (250 mL). Iodine monochloride (30.9 g) wascharged over 2.5 min. The mixture was heated at 50° C. for 3 hours.After cooling to ambient temperature, the mixture was filtered. The cakewas re-slurried in methanol (250 mL) and heated to 50° C. for 3 hours.After cooling to ambient temperature, the mixture was filtered and thefilter cake was washed with methanol (50 mL). The off-white solid wasdried in a vacuum oven at 50° C. to provide1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione1b (32.5 g, 90% yield). LCMS (ESI) m/z 429.3 (MH+). The material may bere-slurried in MeOH as needed.

Step 1C:5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

To a reactor was charged1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione1b (20.0 kg), 2-fluoro-3-methoxyphenylboronic acid (8.7 kg), and acetone(60 L). The mixture was agitated and cooled to 15° C. and a potassiumhydroxide/water solution (10.8 kg/64 L) was charged. The reactorcontents were degassed for 30 min, then tri-t-butylphosphoniumtetrafluoroborate (142 g) was added to the reactor and the contentsmixed at 45° C. for 20 min. Palladium (II) acetate (52 g) was charged tothe reactor and the contents were mixed at 55° C. The reaction mixturewas stirred until the reaction was complete. Acetic acid (5.6 kg) wascharged to the reactor over 1 hr, then the mixture was stirred at 55° C.for 30 min. The reactor contents were cooled to 25° C. over 2 hr. Thesolid was collected by centrifugation and the cake washed with water (40L) followed by methanol (80 L). The solid was dried in a vacuum oven at50° C. until the loss-on-drying was less than 1% to provide5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1c (16.6 kg, 83% molar yield) as an off-white solid. LCMS (ESI) m/z427.1 (MH+).

Alternate Step 1C:5-(2-Fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

To a reactor was charged1-(2-fluoro-6-trifluoromethyl-benzyl)-5-iodo-6-methyl-1H-pyrimidine-2,4-dione1b (5.0 kg), 2-fluoro-3-methoxyphenylboronic acid (2.58 kg), and acetone(5.5 L). The mixture was agitated and a potassium hydroxide/watersolution (2.658 kg/19.0 L) was charged. The reactor contents weredegassed for 30-60 min, then the internal temperature was adjusted to40° C. 1,1-(bis-di-t-butylphosphino)ferrocene palladium dichloride (11.4g) was added to the reactor and the contents mixed with jackettemperature set to 45° C. until the reaction was complete (2.5 hr). Thereaction mixture was cooled to 20-30° C. Celite (1.25 kg) was charged tothe reactor and stirred for more than one hour and the mixture wasfiltered through a Celite pad (0.51 kg). The reactor and Celite cakewere washed with acetone/water/KOH (2.6 L/7.5 L/0.38 kg). The filteredsolutions were passed through a line filter and added over a period of1-1.5 hr to a mixture of THF/AcOH/Water (15.0 L/7.53 L/5.0 L) maintainedat 62° C. The reactor contents were cooled to 20° C. over 2-3 hr. Themixture was filtered and the cake washed with 60:40 water/MeOH (2×12.6L) followed by methanol (2×16 L). The solid was dried in a vacuum ovenat 65° C. for 18 hr to provide5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1c (4.312 kg, 87% molar yield) as an off-white solid. LCMS (ESI) m/z427.1 (MH+). If necessary, the material may be solubilized, re-treatedwith Celite, and crystallized as above to increase purity.

Step 1D: Methanesulfonic acid(S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester

N-Boc-D-phenylglycinol (17.5 kg), diisopropylethylamine (11.4 kg), andtetrahydrofuran (79 L) were charged to a reactor, agitated, and themixture was cooled to 0° C. Methanesulfonyl chloride (9.3 kg) wascharged while maintaining the temperature below 10° C. Addition lineswere rinsed with 26 L THF. After completion of the reaction, an aqueous0.5 N HCl solution (3.6 kg conc. HCl/67 L water) was charged to thereactor while maintaining temperature below 10° C. After mixing,agitation was stopped and the layers were allowed to separate. Theaqueous layer was discarded and heptane (175 L) was charged and thereactor contents were stirred at 0° C. for 1 hour. The mixture wasfiltered and the cake was washed with heptane (25 L) and dried at 40° C.under vacuum to provide methanesulfonic acid(S)-3-tert-butoxycarbonyl-amino-3-phenyl-propyl ester 1d (21.8 kg, 94%molar yield) as a white solid. LCMS (ESI) m/z 216.0 (M-100(Boc)H+)

Alternate Step 1D: Methanesulfonic acid(S)-3-tert-butoxycarbonylamino-3-phenyl-propyl ester

N-Boc-D-phenylglycinol (5.0 kg), triethylamine (3.55 L), anddimethylformamaide (10.54 L) were charged to a reactor, agitated, andthe mixture was cooled to 0° C. Methanesulfonyl chloride (1.79 L) wascharged through a dip-tube while maintaining the temperature below 5° C.After completion of the reaction, acetone (15.0 L) was charged to thereactor while maintaining temperature below 5° C. Water (12.0 L) wascharged to the mixture over 3 hr, maintaining temperature below 5° C.,during which time crystallization occurred. An additional portion ofwater (18 L) was added while maintaining the temperature below 5° C. Themixture was filtered and the cake was washed with 2:1 (v/v)water:acetone three times (2×10 L, 1×6600 L) and dried between 25-40° C.under vacuum to provide methanesulfonic acid(S)-3-tert-butoxycarbonyl-amino-3-phenyl-propyl ester 1d (6.278 kg,94.5% molar yield) as a white solid. LCMS (ESI) m/z 216.0 (M-100(Boc)H+)

Step 1E:3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

Methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3-phenyl-propylester 1d (19.7 kg),5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1c (16.5 kg), potassium carbonate (powder, 325 mesh, 13.4 kg) and DMF(101 L) were charged to a reactor. The mixture was stirred at 55° C.After reaction completion, the reactor was cooled to 20° C. andisopropyl acetate (132 L) was charged, followed by water (157 L). Afteragitation and settling, the layers were separated and the organic layerwashed with water (87 L). After agitation and settling, the water layerwas removed. To the organic layer was charged methanesulfonic acid (11.2kg) and the reactor contents were heated to 60° C. for 1-2 hours. Thereactor contents were cooled to 20° C. and a solution of potassiumcarbonate/water (26.8 kg/140 L) was added slowly, agitated, and thenallowed to settle prior to separation of layers. The organic layer wastreated with a solution of 85% phosphoric acid/H₂O (22.6 kg/236 kg). Themixture was agitated, allowed to settle, and the layers were separated.The aqueous layer was washed with isopropyl acetate (2×167 kg) and thelayers were separated. A solution of potassium carbonate/water (36.1kg/139 kg) was added slowly to the aqueous layer. Isopropyl acetate (206kg) was charged; the mixture was agitated and then allowed to settle.The aqueous layer was removed and the organic layer was concentrated toprovide a solution of3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1e in isopropyl acetate (125.4 kg, 30.7 kg contained, 86% yield) for usein the next step. LCMS (ESI) m/z 546.2 (MH+)

Alternate Step 1E:3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

Methanesulfonic acid (S)-3-tert-butoxycarbonylamino-3-phenyl-propylester 1d (177.54 g),5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1c (160.0 g), 1,1,3,3-tetramethylguanidine (117.72 mL) and DMF (320 mL)were charged to a reactor. The mixture was stirred at 40° C. Afterreaction completion (48 hr), 85% H₃PO₄/water (129.8 g/960 mL) was addedfollowed by isopropyl acetate (960 mL). After agitation and settling,the layers were separated and the organic layer washed with 85%H₃PO₄/water (43.27 g/48 mL). After agitation and settling, the aqueouslayer was removed and the organic layer washed with water (480 mL).After agitation and settling, the aqueous layer was removed. To theorganic layer was charged water (76 mL) and methanesulfonic acid (108.2g) and the reactor contents were heated to 60° C. for 6 hours. Thereactor contents were cooled to 40° C. and a solution of potassiumcarbonate/water (259.34 g/1360 mL) was added slowly, agitated, and thenallowed to settle prior to separation of layers. The organic layer wastreated with a solution of 85% phosphoric acid/H₂O (129.81 g/1360 mL).The mixture was agitated, allowed to settle, and the layers wereseparated. The aqueous layer was washed with isopropyl acetate (2×1120mL) and the layers were separated. A solution of potassiumcarbonate/water (259.34 g/480 mL) was added slowly to the aqueous layer.Isopropyl acetate (1360 mL) was charged; the mixture was agitated andthen allowed to settle. The aqueous layer was removed and the organiclayer was washed with water (480 mL) and the layers were separated. Theorganic later was filtered through a medium glass frit and thelines/filter were rinsed with 220 mL i-PrOAc. The organic layer wasconcentrated by distillation to approximately 550-750 mL volume. Thissolution was heated at 80° C. and heptane (640 mL) was added over onehour. NBI-54048 crystalline seeds (2.0 g) were charged afterapproximately one third of the heptane charge was complete. Afterheptane addition the mixture was maintained at 80° C. for 2 hr, thencooled to 10° C. over 180 min. The mixture was filtered to provide asolid that was dried under vacuum at 50-60° C. overnight.3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1e (170.9 g, 84% yield) was obtained as a white solid. LCMS (ESI) m/z546.2 (MH+)

Example 2

Step 2A: Ethyl-2-(2′-fluoro-3′-methoxyphenyl)-glyoxylate

N,N,N′,N′,N″-Pentamethyldiethylenetriamine (PMDFT, 36.0 g, 43.5 mL, 208mmol) and anhydrous tetrahydrofuran (THF, 150 mL) were charged into a3-necked 1 L round bottom flask purged with N₂. The solution was chilledto −78° C. with acetone—dry ice. Under continuous agitation and N₂ purgebutyllithium (Bu-Li, 1.6 M solution in hexanes, 130 mL, 208 mmol) wasadded to the solution. Over a period of 30-45 min. 2-fluoroanisol (13.1g, 11.7 mL, 104 mmol) diluted with anhydrous THF (50 mL) was added tothe Bu-Li solution. One hour after the addition of 2-fluoroanisol thereaction mixture was slowly transferred to another 3-necked 1 L roundbottom flask containing diethyloxalate (100 mL, 107.6 g, 736 mmol)diluted with anhydrous THF (100 mL) at −78° C. under N₂ purge.Agitation, −78° C. temp. and N₂ purge were maintained during thetransfer and for one hour after. 85% H₃PO₄ (85 mL) diluted with water(240 mL) was added and the temperature was allowed to increase to roomtemp. The layers were separated and the aqueous phase was extracted withtoluene (400 mL). The organic phases were combined and extracted withportions of water until the aqueous phase was neutral. The organic phasewas evaporated in vacuo to yield an oily residue 2a (˜102 g).

Step 2B: Ethyl-2-fluoro-3-methoxymandelate

The major portion of the crude 2a (90 g) from step 2A was dissolved inMeOH (180 mL) and AcOH (30 mL). Under continuous agitation at roomtemperature, NaBH₄ (9.5 g, 251 mmol) dissolved in DMF (95 mL) was slowlyadded. After completion of the reduction the solvents were removed bymeans of vacuum distillation (e.g. water bath temp. up to 85° C. at 25mbar vacuum). The residue was partitioned between water (85 mL) and Et₂O(240 mL). The organic phase was washed with water (3×90 mL). The aqueousphases were extracted again first with Et₂O (250 mL) then with EtOAc(210 mL) in a “counter current” fashion. The extracts were concentrateddown to oily residues 2b. The distribution of the product in variousextracts is as follows:

1^(st) Et₂O extract: 18.35 g, purity: 81.2%*

2nd Et₂O extract: 2.39 g, purity: 100%*

EtOAc extract: 0.68 g, purity: 65.8%* *The “purity” figures are based onthe second Et₂O extract as 100%.

Step 2C: Ethyl-2-(2′-fluoro-3′-methoxyphenyl)-2-O-mesyl-glycolate

The crude oily concentrates of the ether extracts of 2b (20.7 g) weredissolved in a mixture of MeCN (60 mL) and Et₃N (40 mL). Undercontinuous stirring at room temperature, methanesulfonyl chloride (16.7mL, 24.7 g, 216 mmol) diluted with MeCN (10 mL) was slowly added to thesolution. At the end of the reaction the sample was partitioned betweenwater (130 mL) containing Na₂CO₃ (1.5 g) and Et₂O (315 mL). The aqueousphase was extracted again with Et₂O (100 mL). The organic phases werecombined and evaporated to an oil 2c (24.1 g).

Step 2D: Ethyl-2-bromo-(2′-fluoro-3′-methoxyphenyl)-acetate

The mesyl ester 2c (24.1 g) was dissolved in MeCN (50.0 mL). CrystallineEt₄N⁺.Br (15.2 g, 72.3 mmol) was added to the solution and the mixturewas stirred at room temperature. The conversion was ca. 93% complete infive hours and 100% in four days. The mixture was concentrated to 45-50mL and water (50 mL) was added. The resulting two-phase system wasvigorously stirred while loaded onto a Mitsubishi SP207 (brominatedcross-linked polystyrene) column (300 mL, 23 cm high). The column waseluted in a stepwise gradient manner with mixtures of water/MeCN in thefollowing ratios: 70:30 (500 mL)—60:40 —50:50 —40:60 —35:65 —30:70—25:75 (250 mL each)—20:80 (500 mL)—15:85 and 10:90 (250 mL each). Thefractions were evaluated by TLC first and the fractions containing theproduct were assayed by HPLC. Like fractions were combined and theorganic component was removed by distillation in vacuo. The oily phasesunder the aqueous residues were extracted with CH₂Cl₂. The organicphases were dried to yield 2d as a yellow oil. The yield was calculatedas 11.45 g from assays based on the best fraction available being usedas a standard.

Step 2E: Ethyl-2-(2′-fluoro-3′-methoxyphenyl)-3-aminocrotonate

A sample of bromoacetate 2d (3.48 g, ca. 86% pure based on the purestsample available as standard, 10.3 mmol) was dissolved in HPLC gradeMeCN (10.0 mL). The resulting solution was evaporated to an oily residuein a stream of N₂ at elevated temperature (drying block set at 60° C.).Simultaneously, Zn powder (−100 mesh, 0.714 mg, 10.9 mmol) was suspendedin HPLC grade MeCN (5.0 mL) and was completely dried under the sameconditions as above. All reactants were cooled to room temp. While keptin a strictly inert atmosphere, 2d sample was re-dissolved in anhydrousMeCN (10.0 mL) and transferred to the vial containing Zn powder. Undervigorous agitation the reaction was initiated within the time intervalof 0-10 min. and was complete in 45-60 min. The reaction mixture wascentrifuged to remove excess Zn powder. The supernatant was partitionedbetween toluene (100 mL) and water (70 mL)-AcOH (4.0 mL). The organicphase was washed with water (70 mL) and water (70 mL)-conc. NH₄OH (2.0mL). The organic phase was washed again with water (2×70 mL) andevaporated to an oil 2e (3.99 g, ˜69% pure). LCMS (ESI) m/z 254.5 (MH+)

Example 3

Step 3A:(Z)-2-(2-Fluoro-3-methoxy-phenyl)-3-phenoxycarbonylamino-but-2-enoicacid ethyl ester

Aminocrotonate 2e (5.0 g, 19.7 mmol), toluene (50 mL), calcium oxide(powdered, 2.5 g, 44.6 mmol), and phenyl chloroformate (3.4 g, 21.67mmol) were combined in a reactor. The slurry was stirred at 75° C. for10 hours. The mixture was cooled to 25° C. and filtered through a #1filter paper. The reactor and cake were washed with 50-100 mL oftoluene. The toluene solutions were combined and stripped off under a 10mm vacuum to give 7.5 g of carbamate residue 3a.

Step 3B:N-{(R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-2,2-dimethyl-propionamide

DMF (anhydrous, 70 mL) was added to carbamate residue 3a (7.5 g, 19.7mmol) and the mixture was cooled to 0° C.t-BOC-(1R)-amino-2-amino-1-phenylethane acetate salt (6.41 g, 21.6 mmol)was added followed by K₂CO₃ (4.08 g, 29.6 mmol). The mixture was stirredfor ˜3 hours (all carbamate 3a (t_(R)=11.5 minute in HPLC method 1) wasconverted to urea intermediate (t_(R)=10.5 minute in HPLC method 1)).The temperature was raised to 60° C. to control the CO₂ release. Themixture was heated for 2-3 hours then 210 mL of water was slowly addedover 30-60 minutes maintaining the temperature at 60° C. The slurry wasstirred for 30-60 minutes at 50-60° C. and was cooled down to 25° C.over 30-60 minutes. The slurry was filtered and the cake was washed with210 mL water to remove the residual base. The cake was dried at 10mm/50° C. to give 6.5 g (70% yield) of off-white fine needle crystal 3b.Alternately, the cake may be washed with acetonitrile/water 2:1 beforedrying.

Step 3C:3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

Uracil 3b (14.5 g, 30.9 mmol), sodium carbonate (50.0 g, 106 mmol),sodium bromide (25.0 g, 102.9 mmol), anhydrous DMF (200 mL), and2-fluoro-6-trifluoromethylbenzyl bromide (12.0 g, 46.7 mmol) in 50 mLtoluene were heated at 70-90° C. for 10 hours (HPLC showed all of the 3bwas consumed). The mixture was cooled to room temperature and was slowlycharged with 170 mL of conc. HCl solution. (Optionally, the solidcarbonate and sodium bromide can be filtered off before the addition ofthe HCl resulting in the use of less HCL solution). The solution washeated at 60° C. for 10 hours. The pH of the solution was adjusted to7-8 by slowly adding solid sodium carbonate. 600 mL of DI water wasadded and the solution was extracted with 2×250 mL isopropyl acetate.The phases were separated and the organic layer was washed with 2×100 mLof DI water. The organic layer was concentrated to 150 mL and wasextracted with 150 mL 10% phosphoric acid. The aqueous layer wasagitated with 450 mL of isopropyl acetate and the mixture wasneutralized with saturated sodium bicarbonate solution to pH 7. Thephases were separated and the organic layer was washed with 2×100 mL ofwater then dried over anhydrous sodium sulfate. The organic layer wasfiltered and the filtrate was concentrated at 10 mm and 50-60° C. togive 15.8 g of 1e as sticky oil with >98% HPLC peak are at 254 um(t_(R)=6.61 min, HPLC method 1). The yield was 91%. The oil can betriturated with hexane to further remove some of the impurities.

Example 4

Step 4A:4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester

To a reactor was charged a solution of3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1e in isopropyl acetate (30.7 kg in 125.4 kg solution).Dimethylformamide (28.8 kg) was charged and the mixture was distilledunder vacuum to remove the isopropyl acetate. Ethyl-4-bromobutyrate(11.8 kg) was charged to the reactor followed by diisopropylethylamine(8.87 kg). The reactor contents were heated to 52° C. and stirred untilcompletion of reaction. The reactor was cooled to 22° C. and isopropylacetate (144 kg) and water (144 kg) were added. The mixture was agitatedand the layers allowed to settle. The water layer was removed and theorganic layer was washed with water (144 kg). The organic layer wastreated with a solution of 85% phosphoric acid/H₂O (15.6 kg/173 kg). Themixture was agitated, allowed to settle, and the layers were separated.The organic layer was treated with a solution of 85% phosphoric acid/H₂O(4.03 kg/28.8 kg). The mixture was agitated, allowed to settle, and thelayers were separated. The aqueous phosphate layers were combined andwashed with isopropyl acetate (28.8 kg). After layer separation,isopropyl acetate (144 kg) was added to the aqueous layer, followed byslow addition of a solution of potassium carbonate/water (35.1 kg/43.2kg) while mixing. The layers were separated and the organic layer wasconcentrated by vacuum distillation. The solution was passed through asilica gel plug pre-conditioned with CH₂Cl₂ and the plug eluted usingi-PrOAc/CH₂Cl₂ (31 kg/190 kg) in four portions. Appropriate portionswere combined and the solution was concentrated initially by atmosphericpressure distillation followed by vacuum distillation. The concentratedsolution of4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester 4a (86.4 kg total, ˜29.8 kg of 4a, 80% yield) was usedin the next step. LCMS (ESI) m/z 660.2 (MH+)

Step 4B:4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid

To a reactor was charged a solution of4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester 4a (86.4 kg solution, containing ˜29.8 kg of 4a). Thesolution was concentrated by vacuum distillation, followed by additionof ethanol (59.6 kg). The solution was concentrated by vacuumdistillation. After distillation was complete, ethanol (59.6 kg) wascharged to the reactor, followed by a solution of NaOH/water (4.47kg/59.6 kg). The reactor contents were heated at 35° C. for two hoursuntil reaction completion. The reactor contents were concentrated usingvacuum distillation, water (89.4 kg) was added, and the reactor contentswere concentrated using vacuum distillation. Water (149 kg) was addedand the solution was cooled to 10-15° C. A solution of conc. HCl/water(8.05 kg/29.8 kg) was added slowly over ˜1 hr while maintaining thetemperature between 10-15° C. until the pH was 6.1. The slurry wasstirred at 22° C. for 16 hours and filtered. The reactor and filter cakewere washed with water (2×50 kg) and the solid product was dried undervacuum at 37° C. to provide4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid 4-1 as an off-white solid (26.1 kg, 91% yield). LCMS (ESI) m/z632.2 (MH+)

Example 5

Step 5A:4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester

To a reactor was charged a solution of3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1e in isopropyl acetate (19.0 kg in 59.6 L solution). Dimethylformamide(18 L) was charged and the mixture was distilled under vacuum to removethe isopropyl acetate. Ethyl-4-bromobutyrate (7.83 kg) was charged tothe reactor followed by diisopropylethylamine (5.87 kg). The reactorcontents were heated to 55° C. and stirred until completion of reaction.The reactor was cooled to 20° C. and isopropyl acetate (110 L) and water(96 L) were added. The mixture was agitated and the layers allowed tosettle. The water layer was removed and the organic layer was washedwith water (95 L). The organic layer was treated with a solution of 85%phosphoric acid/H₂O (10.4 kg/152 L). The mixture was agitated, allowedto settle, and the layers were separated. The organic layer was treatedwith a solution of 85% phosphoric acid/H₂O (2.7 kg/19 L). The mixturewas agitated, allowed to settle, and the layers were separated. Theaqueous phosphate layers were combined and washed with isopropyl acetate(21 L). After layer separation, dichloromethane (109 L) was added to theaqueous layer, followed by slow addition of a solution of potassiumcarbonate/water (23.2 kg/29 L) while mixing. The layers were separatedand the organic layer was concentrated by vacuum distillation. Thesolution was passed through a silica gel plug pre-conditioned withCH₂Cl₂ and the plug eluted using EtOH/CH₂Cl₂ (5 L/469 L). Appropriateportions were combined and the solution was concentrated by vacuumdistillation. Ethanol (80 L) was charged to provide a concentrated stocksolution of4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester 4a (82.9 kg total, ˜17.3 kg of 4a, 75% yield) that wasused in the next step. LCMS (ESI) m/z 660.2 (MH+)

Alternate Step 5A:4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester

To a reactor was charged a solution of3-((R)-2-amino-2-phenyl-ethyl)-5-(2-fluoro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione1e (3000 g) and dimethylformamide (4.5 L). The mixture was stirred anddiisopropylethylamine (924 g) and ethyl-4-bromobutyrate (1287 g) werecharged to the reactor and the reactor contents were heated to 80-85° C.After completion of the reaction (4 hr) the contents were cooled to25-30° C. and isopropyl acetate (15.0 L) and water (9.0 L) were added.The mixture was agitated and the layers allowed to settle. The waterlayer was removed and the organic layer was washed with citricacid/water (300 g/6.0 L). The layers were separated and the organiclayer was treated with a solution of 85% phosphoric acid/H₂O (1055g/21.0 L). The mixture was agitated, allowed to settle, and the layerswere separated. The organic layer was treated with a solution of 85%phosphoric acid/H₂O (422 g/6.0 L). The mixture was agitated, allowed tosettle, and the layers were separated. The aqueous phosphate layers werecombined and washed with isopropyl acetate (2×6.0 L). After layerseparation, isopropyl acetate (15.0 L) was added to the aqueous layer,followed by slow addition of a solution of potassium carbonate/water(3.04 kg/4.5 L) while mixing. The layers were separated and the aqueouslayer was extracted with i-PrOAc (6.0 L). After layer separation, thecombined organic layers were washed with sodium bicarbonate/water (1.20kg/15.0 L). Reagent alcohol (6.0 L) was added to the organic layer andthe solution concentrated by vacuum distillation until the reactorvolume was ˜9.0 L. Reagent alcohol (12.0 L) was added and distillationwas resumed until the volume was ˜9.0 L. The concentrated solution of4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester 4a was used in the next step. LCMS (ESI) m/z 660.2(MH+)

Step 5B:4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid sodium salt

To a reactor was charged a stock solution of4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester 4a (81.8 kg solution, containing ˜17.1 kg of 4a). Asolution of NaOH/water (2.2 kg/70 L) was added and the reactor contentswere stirred at 20-25° C. for five hours until reaction completion. Thereactor contents were concentrated using vacuum distillation. Water (124L) was added and the solution was passed through a 5 μm line filter.Methyl isobutyl ketone (120 L) was charged and the mixture heated to 55°C. Separate the layers and add methyl isobutyl ketone (120 L) to theaqueous layer at ambient temperature. Agitate the mixture and add 48%aqueous sodium hydroxide (33 kg). Separate the layers and wash theaqueous layer with methyl isobutyl ketone (51 L). Separate the layersand wash the combined methyl isobutyl ketone layers with an aqueousbrine solution (15.4 kg NaCl/44 L water). Separate the layers andconcentrate the organic layer to ˜2-3 volumes methyl isobutyl ketone.Filter the concentrated solution through a 0.2 μm filter. Charge themethyl isobutyl ketone solution to a well-agitated reactor containingheptane (171 L) cooled to 20° C. The mixture is stirred for two hours,filtered, and the cake is washed with heptane (10 L) to provide4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid sodium salt 5-1 as an off-white solid (13.2 kg, 78% yield). LCMS(ESI) m/z 632.2 (MH+)

Alternate Step 5B:4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid sodium salt

To a reactor was charged a solution of4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester 4a from the previous step. Reagent alcohol (6.0 L) wasadded and the temperature adjusted to 20° C. A solution of NaOH/water(440 g/6.0 L) was added and the reactor contents were stirred at 20-25°C. for two hours until reaction completion. Water (9.0 L) was added andthe reactor contents were concentrated using vacuum distillation to avolume of approximately 15.0 L. Water (15.0 L) and methyl isobutylketone (9.0 L) was charged, the mixture was agitated, the layers wereseparated, and the aqueous layer was retained. A second wash with methylisobutyl ketone may be performed if needed. Methyl isobutyl ketone (9.0L) was added and the mixture concentrated by vacuum distillation to avolume of approximately 30 L and ethanol content less than 3%. Thereactor contents were set to a temperature of 25-30° C. and sodiumchloride (4507 g) and methyl isobutyl ketone (21.0 L) were charged tothe reactor and agitated. The layers were separated and the organiclayer was concentrated to ˜2-3 volumes methyl isobutyl ketone. Theconcentrated solution was filtered through Celite and a 0.3 μm linefilter. The filtered solution was charged to a well-agitated reactorcontaining heptane (30.0 L) cooled to 10-20° C. The mixture was stirredfor two hours, filtered, and the cake was washed with heptane (8 L). Theproduct was dried in a vacuum oven for 24-48 hr at 70-75° C. to provide4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid sodium salt 5-1 as an off-white solid (2.46 kg, 64% yield). LCMS(ESI) m/z 632.2 (MH+)

Example 6

Step 6A

To a stock solution of4-((R)-2-[5-(2-fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester (˜6.55 g, 9.94 mmol) in i-PrOAc (140 mL) was addedconc. HCl (12 N, 0.88 mL, 10.6 mmol) solution in water dropwise at roomtemperature over 2 min. Approximately 95 mL of water and i-PrOAc mixturewas removed by distillation under reduced pressure. Isopropyl alcohol(1.28 mL) was added to provide a homogeneous solution at 28° C. Thereaction mixture was added dropwise into a vigorously stirred solutionof n-heptane (65 mL) at 5° C. A white precipitate was formed immediatelyand the mixture became thick upon completion of addition. The whiteslurry was stirred for 18 h at room temperature. The white solid wascollected by pressure filtration under nitrogen and dried by passingnitrogen through the filter cake for 1 h to provide 6.0 g (87%) of4-((R)-2-[5-(2-Fluoro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester HCl salt 4a.HCl as a white solid, LCMS (ESI) m/z 660.2(MH+ of free base). Elemental analysis: Cl, 5.21%

Example 7

Step 7A:2-(2-Chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

To a stirred solution of2-chloro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (830 g,3.26 mol) in dry DMF (4.15 L) was added potassium carbonate (1126.4 g,8.15 mol) under an inert atmosphere. Me₂SO₄ (402 mL, 4.24 mol) was addedslowly to control the resulting exotherm (addition over 30 minutes gavea temperature rise from 28° C. to 55° C.) and after complete additionthe reaction was stirred for 10 minutes. The reaction mixture was addedto stirring HCl (5.98 L, 2 N, aq.) very slowly to control effervescenceand the resulting precipitate stirred for 2 hours. The solids werefiltered and washed with water (1 L) and dried in a vacuum oven overdrying agent for 4 days to give2-(2-chloro-3-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane7a as a white powder (746.7 g, 2.78 mol, 85%).

Step 7B:5-(2-Chloro-3-methoxy-phenyl)-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

Compound 1b (80 g, 0.19 mol), 7a (60.22 g, 0.22 mol), HP(t-Bu)₃BF₄(13.01 g, 44.85 mmol), and Pd₂(dba)₃ (13.69 g, 14.95 mmol) were chargedto the reaction vessel and purged with an inert atmosphere. Degassed THF(560 mL) was added followed by NaOH (31.45 g, 0.56 mol) in degassedwater (128.8 mL) and the reaction warmed to 45° C. After 2 hours aceticacid (56 mL) was added and stirred for 15 minutes. After settling, thelayers were separated and the organic layer was filtered through celite,rinsing with hot THF (2×160 mL). The filtrate was concentrated in vacuoto a slurry, to which was added N-acetyl cysteine (15.84 g) as asolution in water (160 mL) and ethanol (640 mL) and stirred for 2 hoursat 75° C. under an inert atmosphere. The slurry was cooled to RT, andthe solids filtered off, washed with ethanol:water (8:2, 2×160 mL) togive5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione7b as a white solid (58.6 g, 0.13 mol, 70%).

Step 7C:3-((R)-2-Amino-2-phenyl-ethyl)-5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione

7b (120 g, 0.271 mol), 1d (128.34 g, 0.407 mol) and K₂CO₃ (93.64 g,0.407 mol) were charged to the reaction vessel under an inert atmosphereand suspended in DMF. The resulting slurry was warmed to 50° C. andstirred for 17 hours. The reaction was incomplete so additional 1d (50g, 0.158 mol) and DMF (300 mL) were added. The reaction was completeafter 32 hours and the mixture was cooled to RT. i-PrOAc (1 L) and water(1 L) were added and stirred for 30 minutes. The layers were separatedand MeSO₃H (52.8 mL, 0.813 mol) was added slowly to the organic layercontrolling the exotherm (24.4° C. to 41.0° C.). The mixture warmed to60° C. and was stirred for 3 hours. The mixture was cooled to RT and wasadded slowly to a mixture of K₂CO₃ (186.99 g, 1.35 mol) in water (975mL). After stirring for 15 minutes, the organic layer was separated andextracted with a H₃PO₄ solution (94 g of 85% H₃PO₄ in 975 mL water). Theaqueous layer was slowly added to K₂CO₃ (186.99 g, 1.35 mol) in water(975 mL), followed by i-PrOAc (1100 mL). The mixture was stirred for 10minutes and the layers separated. The i-PrOAc layer was dried (NaSO₄)and concentrated to give3-((R)-2-amino-2-phenyl-ethyl)-5-(2-chloro-3-methoxy-phenyl)-1-(2-fluoro-6-methyl-benzyl)-6-methyl-1H-pyrimidine-2,4-dione7c as a foaming solid (145.5 g, 0.25 mol, 95% crude yield, uncorrectedfor purity).

Step 7D:4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester

7c (145.5 g, 0.259 mol) was dissolved in DMF (146 mL) under an inertatmosphere. 4-Bromobutyrate (42.6 mL, 0.298 mol) was added followed byi-Pr₂EtN (58.65 mL, 0.337 mol) and was stirred overnight at 54° C. Themixture was cooled to RT and i-PrOAc (620 mL), water (620 mL) wereadded, and the mixture was stirred for 30 minutes. After separation, theorganic layer was washed with water (620 mL) and extracted with a H₃PO₄solution (67.3 g of 85% H₃PO₄ in 1 L water). The organic was extracted asecond time with a H₃PO₄ solution (17.6 g of 85% H₃PO₄ in 126 mL water).The combined aqueous phosphate extracts were washed with i-PrOAc (130mL). CH₂Cl₂ (950 mL) was added to the aqueous phosphate layer followedby a slow addition of a solution of K₂CO₃ (172 g, 1.24 mol) in water(188 mL). The mixture was stirred for 30 minutes and after separationthe organic dried (NaSO₄) and concentrated in vacuo to give4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid ethyl ester 7d as a foaming oil (121 g, 0.179 mol, 70%).

Step 7E:4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid sodium salt

NaOH (338 mL, 169 mmol, 0.5 M aq.) was added to a solution of 7d (103.9g, 153.68 mol) in EtOH (472 mL) and the mixture was stirred for 2 hours.The EtOH was distilled off and water added to a total volume of 1080 mL(10.5 mL/g). This mixture was passed through a filter and washed withMIBK (600 mL×2). MIBK (700 mL) was added followed by NaOH (289 mL, 50%w/w) and extracted. The organic layer was separated and the aqueousextracted with MIBK (250 mL) and the combined organic layers washed withbrine (500 mL), dried (NaSO₄) and concentrated in vacuo to give a foam.This was lyophilized from 300 mL water to give4-((R)-2-[5-(2-chloro-3-methoxy-phenyl)-3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethylamino)-butyricacid sodium salt 7-1 as an off white powder (92 g).

Example 8 Spray Drying Compound 5-1

Compound 5-1 was spray dried in a Buchi Mini Spray Dryer model B-290. Inthe B-290, compound 5-1 was dried co-currently with the drying gasflowing at approximately 30 m³/hr. The B-290's spraying chamber wasabout 5.5 liters. Therefore, the B-290's average drying residence timewas about 0.6 sec. Atomization was achieved by passing nitrogen gas andfeed stream through a two fluid nozzle atomizer.

Several drying runs were conducted using different solvents andadjusting the pH. The following table shows the conditions of runs. Allruns resulted in an amorphous solid with no change in impurity profile.

Cmpd Inlet Outlet 5-1 temp temp Run # (g) (° C.) (° C.) Solvent 1 2 8v/w 50:50 EtOH:H₂O 2 2 110 55 8 v/w H₂O 3 2 110 64 8 v/w 60:40 H₂O:EtOH4 2 100 54 8 v/w 50:50 MeOH:H₂O 5 2 70 49 8 v/w MeOH 6 2 100 55 8 v/w50:50 MeOH:H₂O, XS NaOH 7 2 100 57 8 v/w 50:50 MeOH:H₂O 8 4 110 65 ~12v/w 50:50 MeOH:H₂O 9 4 110 59 ~6 v/w 50:50 MeOH:H₂O, XS NaOHAll trials run with N₂ flow of ˜30 m³/hr, atomization flow of 0.45m³/hr, and solution feed rate of approx. 5 mL/min

Example 9 Formation of Solid Amorphous Mixtures of Compound 5-1 UsingSolvent Evaporation

Appropriate amounts of compound 5-1 and polymer were dissolved by bathsonication in a solvent system comprising DCM/ethanol 1:1 (w/w), in a250 mL Quickfit round bottomed flask. The solvent was then removed asrapidly as possible under vacuum. The vacuum was maintained until allobvious traces of the solvent had been removed, and was then transferredto a freeze drier chamber and left overnight at high vacuum. The driedmaterial was removed from the flask using a spatula and analyzed foramorphous content using XRPD and DSC. Compound 5-1 was recovered as anamorphous solid mixture with polymer.

Run # Polymer:compound 5-1 ratio Polymer 1 3:1 Kollidon 30 2 3:1Kollidon 90 F 3 3:1 HPMC 4 3:1 Kollidon 30 5 3:1 Kollidon 90 F 6 3:1HPMC

It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention. Accordingly, the invention is not limited exceptas by the appended claims.

What is claimed is:
 1. A process for preparing a compound of structure(VI):

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:R_(1a), R_(1b) and R_(1c) are the same or different and independentlyhydrogen, halogen, C₁₋₄alkyl, hydroxy or alkoxy; R_(2a) and R_(2b) arethe same or different and independently hydrogen, halogen,trifluoromethyl, cyano or —SO₂CH₃; R₃ is hydrogen or methyl; and R₄ isH, —C₁₋₆alkanediyl-COOH, or —C(═O)O-(t-butyl); comprising as anintermediate synthesis step: reacting a compound of structure (VII):

wherein R₂a, R_(2b) and R₃ are as defined above; with a compound ofstructure (VIII):

wherein R is H or C₁₋₄-alkyl, R′ is H or C₁₋₄-alkyl or R and R′ takentogether form C₁₋₆alkanediyl; and R_(1a), R_(1b), and R_(1c) are asdefined above; and reacting methanesulfonicacid-(S)-3-tert-butoxycarbonyl-amino-3-phenyl-propyl ester with thecompound formed by reacting compound (VII) with compound (VIII), whichcompound has the structure:

in the presence of a base.
 2. The process of claim 1 wherein saidreaction of said compound of structure (VII) with said compound ofstructure (VIII) occurs in the presence of a palladium catalyst.
 3. Theprocess of claim 1 wherein R_(1a) is halogen, R_(1b) is methoxy andR_(1c) is H.
 4. The process of claim 3 wherein R_(2a) is halogen andR_(2b) is halogen or trifluoromethyl.
 5. The process of claim 1, furthercomprising isolation of a compound of formula (VI) as an amorphoussolid.